Eptifibatide is a cyclic heptapeptide used for the treatment of cardio vascular disease. It is a short acting parenteral antithrombotic drug used for treating Acute Coronary Syndrome (ACS). It is also used in patients undergoing Percutaneous Coronary Intervention (PCI). Eptifibatide is an anti-platelet agent with high affinity and specificity for the Glycoprotein (GP) IIb/IIIa receptor that mediates platelet aggregation. Eptifibatide is an inhibitor of platelet aggregation and belongs to a new class of RGD mimetics-arginine (R), glycine (G), aspartic acid (D). Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to the GP IIb/IIIa receptors.
Eptifibatide is commercially available in United States under the brand name of Integrilin which is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 24 hours and with ECG changes and/or elevated cardiac enzymes. Integrilin is intended for use with acetylsalicyclic acid and unfractionated heparin.
Integrilin is formulated as a sterile solution for intravenous (IV) injection in a single dose of 20 mg/10 ml vial, and as a sterile solution for IV continuous infusion of 75 mg/100 ml vial. The recommended dose is an intravenous bolus of 180 μg/kg administered as soon as possible following diagnosis, followed by a continuous infusion of 2 μg/kg for upto 72 hours (96 hours in patients undergoing coronary angioplasty).
Eptifibatide is chemically synthesized and is a cyclic heptapeptide containing six aminoacids and one thioalkyl carboxylic acid (desamino cysteinyl) residue. The active ingredient is a cyclic heptapeptide that has a molecular weight of 831.96 daltons. It is soluble in water, methanol and ethanol.
Over the years, short synthetic peptides have gained great therapeutic significance in treating life threatening diseases. Eptifibatide, Bivalirudin, Enfuviritide, and Exenatide are some of them.
Market faces the challenge to produce peptides in Kilo quantities and greater than 100 kilograms. In terms of peptide synthesis methodology, two major synthetic techniques dominate current practice. These are solution phase, and solid-phase syntheses.
The Fmoc strategy of solid phase peptide synthesis and orthogonal protection groups opened the door for the rapid synthesis of long peptides wherein physical-chemical properties are controlled, the process is amicable to automation and scalable, and no isolation of intermediates is required with short production cycles. But expensive raw materials generating a complex impurity profile are constant threats to techno-commercial processes.
At present the proven scalability of peptide chemistry is upto 1000 L reactors. The supplier customer relationship is becoming more and more complex requiring an intensive collaboration throughout the whole life cycle of product. The high volume high value peptide such as bivalirudin and Eptifibatide drive very few established API manufacturers such as Lonza and Peptisyntha due to large scale market size with an estimated API demand of 100 kilos and commercial viability of the process.
The Eptifibatide product patent expiry is targeted in US in September 2015. There is Para IV filed by Teva against the Orange Book listed method of use patents. In the current scenario, to tackle the increasing market growth and to cater the demand, an efficient cost-effective process for synthesis of Active Pharmaceutical Ingredient is the need of the hour.
The present invention targets a cost-effective novel strategy for large scale synthesis of this cyclic heptapeptide i.e. Eptifibatide acetate. The present invention relates to a process for large scale synthesis of Eptifibatide using C1-C4 alcohols as total substitute to organic nitriles thus making the process cost effective, non-toxic and eco-friendly.